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1
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Chaqour B, Rossman JB, Meng M, Dine KE, Ross AG, Shindler KS. SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration. Sci Rep 2025; 15:13585. [PMID: 40253451 PMCID: PMC12009334 DOI: 10.1038/s41598-025-97456-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 04/04/2025] [Indexed: 04/21/2025] Open
Abstract
Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.
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MESH Headings
- Animals
- Sirtuin 1/genetics
- Sirtuin 1/metabolism
- Mice
- Mitochondria/metabolism
- Mitochondria/genetics
- Retinal Ganglion Cells/metabolism
- Retinal Ganglion Cells/pathology
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/therapy
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Retinal Degeneration/genetics
- Retinal Degeneration/therapy
- Retinal Degeneration/pathology
- Retinal Degeneration/metabolism
- Mitophagy/genetics
- Mice, Inbred C57BL
- Genetic Therapy
- Gene Regulatory Networks
- Female
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Affiliation(s)
- Brahim Chaqour
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
| | - Jacob B Rossman
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Miranda Meng
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kimberly E Dine
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ahmara G Ross
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kenneth S Shindler
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA
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2
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Mora I, Teixidó A, Vázquez-Manrique RP, Puiggròs F, Arola L. Docosahexaenoic Acid (DHA) Supplementation in a Triglyceride Form Prevents from Polyglutamine-Induced Dysfunctions in Caenorhabditis elegans. Int J Mol Sci 2024; 25:12594. [PMID: 39684306 DOI: 10.3390/ijms252312594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
A common hallmark of neurodegenerative diseases is the accumulation of polypeptide aggregates in neurons. Despite the primary cause of these diseases being inherently genetic, their development can be delayed with proper preventive treatments. Long-chain polyunsaturated fatty acids (ω-3 LCPUFA) are promising bioactive nutrients that are beneficial for brain health. In this study, the impact of an oil rich in a structured form of docosahexaenoic acid (DHA) triglyceride (TG) was assessed in a Caenorhabditis elegans model expressing long poly-glutamine (polyQ) chains, which mimics the symptomatology of polyQ-related neurodegenerative diseases such as Huntington's disease (HD), among others. The lifespan, the motility, the number of polyQ aggregates, the oxidative stress resistance, and the cognitive performance associated with sensitive stimuli was measured in mutant nematodes with polyQ aggregates. Overall, DHA-TG at 0.5 µM improved the lifespan, the motility, the oxidative stress resistance, and the cognitive performance of the nematodes, emphasizing the protection against serotonergic synapse dysfunction. Furthermore, the treatment reduced the polyQ aggregates in the nematodes. The data described herein shed light on the connection between DHA and the cognitive performance in neurodegenerative diseases and demonstrated the potential of DHA-TG as nutritional co-adjuvant to prevent the development of polyQ-associated dysfunctions.
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Affiliation(s)
- Ignasi Mora
- Brudy Technology S.L., 08006 Barcelona, Spain
- Universitat Rovira i Virgili, 43003 Tarragona, Spain
| | - Alex Teixidó
- Eurecat, Centre Tecnològic de Catalunya, Nutrition and Health Unit, 43204 Reus, Spain
| | - Rafael P Vázquez-Manrique
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
- Joint Unit for Rare Diseases, Insituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Francesc Puiggròs
- Eurecat, Centre Tecnològic de Catalunya, Biotechnology Area, 43204 Tarragona, Spain
| | - Lluís Arola
- Nutrigenomics Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, 43007 Tarragona, Spain
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3
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Balducci M, Pérez JT, del Río CT, Pérez MC, Carranza ADV, Gomez Escribano AP, Vázquez-Manrique RP, Tarozzi A. Erucin, a Natural Isothiocyanate, Prevents Polyglutamine-Induced Toxicity in Caenorhabditis elegans via aak-2/AMPK and daf-16/FOXO Signaling. Int J Mol Sci 2024; 25:12220. [PMID: 39596283 PMCID: PMC11594550 DOI: 10.3390/ijms252212220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/31/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Several neurodegenerative diseases (NDDs), such as Huntington's disease, six of the spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy, are caused by abnormally long polyglutamine (polyQ) tracts. Natural compounds capable of alleviating polyQ-induced toxicity are currently of great interest. In this work, we investigated the modulatory effect against polyQ neurotoxic aggregates exerted by erucin (ERN), an isothiocyanate naturally present in its precursor glucoerucin in rocket salad leaves and in its oxidized form, sulforaphane (SFN), in broccoli. Using C. elegans models expressing polyQ in different tissues, we demonstrated that ERN protects against polyQ-induced toxicity and that its action depends on the catalytic subunit of AMP-activated protein kinase (aak-2/AMPKα2) and, downstream in this pathway, on the daf-16/FOXO transcription factor, since nematodes deficient in aak-2/AMPKα2 and daf-16 did not respond to the treatment, respectively. Although triggered by a different source of neurotoxicity than polyQ diseases, i.e., by α-synuclein (α-syn) aggregates, Parkinson's disease (PD) was also considered in our study. Our results showed that ERN reduces α-syn aggregates and slightly improves the motility of worms. Therefore, further preclinical studies in mouse models of protein aggregation are justified and could provide insights into testing whether ERN could be a potential neuroprotective compound in humans.
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Affiliation(s)
- Martina Balducci
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy
| | - Julia Tortajada Pérez
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
| | - Cristina Trujillo del Río
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
| | - Mar Collado Pérez
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
| | - Andrea del Valle Carranza
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
| | - Ana Pilar Gomez Escribano
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
- Centro de Investigación Biomédica en Red (CIBER), 28029 Madrid, Spain
| | - Rafael P. Vázquez-Manrique
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46012 Valencia, Spain; (J.T.P.); (C.T.d.R.); (M.C.P.); (A.d.V.C.); (A.P.G.E.); (R.P.V.-M.)
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
- Centro de Investigación Biomédica en Red (CIBER), 28029 Madrid, Spain
| | - Andrea Tarozzi
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy
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4
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Pandaram A, Paul J, Wankhar W, Thakur A, Verma S, Vasudevan K, Wankhar D, Kammala AK, Sharma P, Jaganathan R, Iyaswamy A, Rajan R. Aspartame Causes Developmental Defects and Teratogenicity in Zebra Fish Embryo: Role of Impaired SIRT1/FOXO3a Axis in Neuron Cells. Biomedicines 2024; 12:855. [PMID: 38672209 PMCID: PMC11048232 DOI: 10.3390/biomedicines12040855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells.
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Affiliation(s)
- Athiram Pandaram
- Department of Physiology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai 600113, Tamil Nadu, India
| | - Jeyakumari Paul
- Department of Physiology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai 600113, Tamil Nadu, India
| | - Wankupar Wankhar
- Faculty of Paramedical Sciences, Assam down town University, Guwahati 781026, Assam, India
| | - Abhimanyu Thakur
- Pritzker School of Molecular Engineering, Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Sakshi Verma
- Department of Pharmacy, Usha Martin University, Ranchi 835103, Jharkhand, India
| | - Karthick Vasudevan
- Department of Biotechnology, REVA University, Bangalore 560064, Karnataka, India
| | - Dapkupar Wankhar
- Faculty of Paramedical Sciences, Assam down town University, Guwahati 781026, Assam, India
| | - Ananth Kumar Kammala
- Department of Obstetrics and Gynaecology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Priyanshu Sharma
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ravindran Jaganathan
- Preclinical Department, Faculty of Medicine, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Perak, Malaysia
| | - Ashok Iyaswamy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
| | - Ravindran Rajan
- Department of Physiology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai 600113, Tamil Nadu, India
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5
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Shimokawa I. Mechanisms underlying retardation of aging by dietary energy restriction. Pathol Int 2023; 73:579-592. [PMID: 37975408 PMCID: PMC11551835 DOI: 10.1111/pin.13387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 10/19/2023] [Indexed: 11/19/2023]
Abstract
Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone-insulin-like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor-inhibiting and life-extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO- and Npy-associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.
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Affiliation(s)
- Isao Shimokawa
- Department of Pathology INagasaki University School of Medicine and Graduate School of Biomedical SciencesNagasakiJapan
- SAGL, LLCFukuokaJapan
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6
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Merino M, Sequedo MD, Sánchez-Sánchez AV, Clares MP, García-España E, Vázquez-Manrique RP, Mullor JL. Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease. Int J Mol Sci 2022; 23:8936. [PMID: 36012207 PMCID: PMC9409211 DOI: 10.3390/ijms23168936] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 12/04/2022] Open
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.
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Affiliation(s)
- Marián Merino
- Bionos Biotech SL, Biopolo Hospital La Fe, 46026 Valencia, Spain
| | - María Dolores Sequedo
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | | | - Mª Paz Clares
- Departamento de Química Orgánica e Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, 46980 Valencia, Spain
| | - Enrique García-España
- Departamento de Química Orgánica e Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, 46980 Valencia, Spain
| | - Rafael P. Vázquez-Manrique
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Joint Unit for Rare Diseases IIS La Fe-CIPF, 46012 Valencia, Spain
| | - José L. Mullor
- Bionos Biotech SL, Biopolo Hospital La Fe, 46026 Valencia, Spain
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7
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Wang R, Wu Y, Liu R, Liu M, Li Q, Ba Y, Huang H. Deciphering therapeutic options for neurodegenerative diseases: insights from SIRT1. J Mol Med (Berl) 2022; 100:537-553. [PMID: 35275221 DOI: 10.1007/s00109-022-02187-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 12/23/2022]
Abstract
Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD +)-dependent protein deacetylase that exerts biological effects through nucleoplasmic transfer. Recent studies have highlighted that SIRT1 deacetylates protein substrates to exert its neuroprotective effects, including decreased oxidative stress and inflammatory, increases autophagy, increases levels of nerve growth factors (correlated with behavioral changes), and maintains neural integrity (affects neuronal development and function) in aging or neurological disorder. In this review, we highlight the molecular mechanisms underlying the protective role of SIRT1 in modulating neurodegeneration, focusing on protein homeostasis, aging-related signaling pathways, neurogenesis, and synaptic plasticity. Meanwhile, the potential of targeting SIRT1 to block the occurrence and progression of neurodegenerative diseases is also discussed. Taken together, this review provides an up-to-date evaluation of our current understanding of the neuroprotective mechanisms of SIRT1 and also be involved in the potential therapeutic opportunities of AD and related neurodegenerative diseases.
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Affiliation(s)
- Ruike Wang
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Yingying Wu
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Rundong Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Mengchen Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Qiong Li
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Yue Ba
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China.,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China
| | - Hui Huang
- Department of Environmental Health, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Henan province, Zhengzhou, 450001, China. .,Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Henan province, Zhengzhou, 450001, China.
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8
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Behl T, Arora A, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:542-556. [PMID: 34758720 DOI: 10.2174/1871527320666211110115257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/25/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022]
Abstract
Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer's Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer's Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer's Disease as 'brain diabetes'. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer's Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Arpita Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Haryana. India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa. Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea. Romania
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA. United States
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9
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Alì S, Davinelli S, Accardi G, Aiello A, Caruso C, Duro G, Ligotti ME, Pojero F, Scapagnini G, Candore G. Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals. Mech Ageing Dev 2021; 200:111592. [PMID: 34710375 DOI: 10.1016/j.mad.2021.111592] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/06/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022]
Abstract
Mediterranean diet (MedDiet) is rich in fruits and vegetables associated with longevity and a reduced risk of several age-related diseases. It is demonstrated that phytochemicals in these plant products enhance the positive effects of MedDiet by acting on the inflammatory state and reducing oxidative stress. Evidence support that these natural compounds act as hormetins, triggering one or more adaptive stress-response pathways at low doses. Activated stress-response pathways increase the expression of cytoprotective proteins and multiple genes that act as lifespan regulators, essential for the ageing process. In these ways, the hormetic response by phytochemicals such as resveratrol, ferulic acid, and several others in MedDiet might enhance cells' ability to cope with more severe challenges, resist diseases, and promote longevity. This review discusses the role of MedDiet phytochemicals in healthy ageing and the prevention of age-related diseases.
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Affiliation(s)
- Sawan Alì
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Sergio Davinelli
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giulia Accardi
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Anna Aiello
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Calogero Caruso
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy.
| | - Giovanni Duro
- Institute for Research and Biomedical Innovation, National Research Council, Palermo, Italy
| | - Mattia Emanuela Ligotti
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy; Institute for Research and Biomedical Innovation, National Research Council, Palermo, Italy
| | - Fanny Pojero
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Giovanni Scapagnini
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giuseppina Candore
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
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10
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Fisher RS, Jimenez RM, Soto E, Kalev D, Elbaum-Garfinkle S. An apparent core/shell architecture of polyQ aggregates in the aging Caenorhabditis elegans neuron. Protein Sci 2021; 30:1482-1486. [PMID: 33966305 DOI: 10.1002/pro.4105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 01/28/2023]
Abstract
Huntington's disease is caused by a polyglutamine (polyQ) expansion in the huntingtin protein which results in its abnormal aggregation in the nervous system. Huntingtin aggregates are linked to toxicity and neuronal dysfunction, but a comprehensive understanding of the aggregation mechanism in vivo remains elusive. Here, we examine the morphology of polyQ aggregates in Caenorhabditis elegans mechanosensory neurons as a function of age using confocal and fluorescence lifetime imaging microscopy. We find that aggregates in young worms are mostly spherical with homogenous intensity, but as the worm ages aggregates become substantially more heterogeneous. Most prominently, in older worms we observe an apparent core/shell morphology of polyQ assemblies with decreased intensity in the center. The fluorescence lifetime of polyQ is uniform across the aggregate indicating that the dimmed intensity in the assembly center is most likely not due to quenching or changes in local environment, but rather to displacement of fluorescent polyQ from the central region. This apparent core/shell architecture of polyQ aggregates in aging C. elegans neurons contributes to the diverse landscape of polyQ aggregation states implicated in Huntington's disease.
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Affiliation(s)
- Rachel S Fisher
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA
| | - Rosa Meyo Jimenez
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA
| | - Elizabeth Soto
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA
| | - Darin Kalev
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA
| | - Shana Elbaum-Garfinkle
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA.,Ph.D. Programs in Biochemistry and Biology, The Graduate Center, CUNY, New York, New York, USA
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11
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Khan H, Tiwari P, Kaur A, Singh TG. Sirtuin Acetylation and Deacetylation: a Complex Paradigm in Neurodegenerative Disease. Mol Neurobiol 2021; 58:3903-3917. [PMID: 33877561 DOI: 10.1007/s12035-021-02387-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/05/2021] [Indexed: 11/26/2022]
Abstract
Sirtuins are the class III of histone deacetylases that depend on nicotinamide adenine dinucleotide for their activity. Sirtuins can influence the progression of neurodegenerative disorders by switching between deacetylation and acetylation processes. Histone acetylation occurs when acetyl groups are added to lysine residues on the N-terminal part of histone proteins. Deacetylation, on the other hand, results in the removal of acetyl groups. Pharmacological modulation of sirtuin activity has been shown to influence various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. In this review, mechanistic perspective of sirtuins has been discussed in anti-inflammatory, antiapoptotic, and neuroprotective effects in various disorders. We have discussed the structure, neurobiology, and physiology of sirtuins in neurodegenerative disease. Recent preclinical and clinical studies and their outcome have also been elucidated. The aim of this review is to fill in the gaps in our understanding of sirtuins' role in histone acetylation and deacetylation in all neurodegenerative diseases. Here, we emphasized on reviewing all the studies carried out in various labs depicting the role of sirtuin modulators in neuroprotection and highlighted the ideas that can be considered for future perspectives. Taken together, sirtuins may serve as a promising therapeutic target for the treatment of neurodegenerative disorders.
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Affiliation(s)
- Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Palak Tiwari
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
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12
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Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway. Int J Mol Sci 2021; 22:ijms22083884. [PMID: 33918672 PMCID: PMC8069648 DOI: 10.3390/ijms22083884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 12/14/2022] Open
Abstract
Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.
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13
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Voisin J, Farina F, Naphade S, Fontaine M, Tshilenge K, Galicia Aguirre C, Lopez‐Ramirez A, Dancourt J, Ginisty A, Sasidharan Nair S, Lakshika Madushani K, Zhang N, Lejeune F, Verny M, Campisi J, Ellerby LM, Neri C. FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16 INK4a increase. Aging Cell 2020; 19:e13226. [PMID: 33156570 PMCID: PMC7681055 DOI: 10.1111/acel.13226] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 06/26/2020] [Accepted: 07/26/2020] [Indexed: 12/21/2022] Open
Abstract
Neurodegenerative diseases (ND) have been linked to the critical process in aging—cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3‐ETS2‐p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.
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Affiliation(s)
- Jessica Voisin
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | - Francesca Farina
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | | | - Morgane Fontaine
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | | | | | | | - Julia Dancourt
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | - Aurélie Ginisty
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | - Satish Sasidharan Nair
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | | | | | - François‐Xavier Lejeune
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | - Marc Verny
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
| | - Judith Campisi
- Buck Institute for Research on Aging Novato CA USA
- Lawrence Berkeley National Laboratory Berkeley CA USA
| | | | - Christian Neri
- Centre National de la Recherche Scientifique UMR 8256 Institut National de la Santé et de la Recherche Médicale ERL U1164 Assistance Publique‐Hôpitaux de Paris Brain‐C Lab Sorbonne Université Paris France
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14
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Gómez-Escribano AP, Bono-Yagüe J, García-Gimeno MA, Sequedo MD, Hervás D, Fornés-Ferrer V, Torres-Sánchez SC, Millán JM, Sanz P, Vázquez-Manrique RP. Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans. Pharmacol Res 2020; 161:105105. [PMID: 32739430 PMCID: PMC7755709 DOI: 10.1016/j.phrs.2020.105105] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/14/2020] [Accepted: 07/21/2020] [Indexed: 12/29/2022]
Abstract
Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKβ1. In addition, we used an RNAi strategy to silence the expression of the second AMPKβ subunit in worms, namely aakb-2/AMPKβ2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKβ2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.
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Affiliation(s)
- A P Gómez-Escribano
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain; Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain; Joint Unit for Rare Diseases IIS La Fe-CIPF, Valencia, Spain
| | - J Bono-Yagüe
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain; Joint Unit for Rare Diseases IIS La Fe-CIPF, Valencia, Spain
| | - M A García-Gimeno
- Department of Biotechnology, Escuela Técnica Superior De Ingeniería Agronómica y Del Medio Natural (ETSIAMN), Universitat Politécnica De València, Valencia, Spain
| | - M D Sequedo
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain; Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain; Joint Unit for Rare Diseases IIS La Fe-CIPF, Valencia, Spain
| | - D Hervás
- Department of Biostatistics, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - V Fornés-Ferrer
- Tau Analytics, Parc Científic De La Universitat De València, Paterna, Spain
| | - S C Torres-Sánchez
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain
| | - J M Millán
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain; Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain; Joint Unit for Rare Diseases IIS La Fe-CIPF, Valencia, Spain
| | - P Sanz
- Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain; Instituto De Biomedicina De València, CSIC, Valencia, Spain
| | - R P Vázquez-Manrique
- Laboratory of Molecular, Cellular and Genomic Biomedicine, Instituto De Investigación Sanitaria La Fe, Valencia, Spain; Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain; Joint Unit for Rare Diseases IIS La Fe-CIPF, Valencia, Spain.
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15
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Xia SR, Wen XY, Fan XL, Chen XR, Wei ZW, Li QH, Sun L. Wnt2 overexpression protects against PINK1 mutant‑induced mitochondrial dysfunction and oxidative stress. Mol Med Rep 2020; 21:2633-2641. [PMID: 32323790 DOI: 10.3892/mmr.2020.11066] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 03/12/2020] [Indexed: 11/06/2022] Open
Abstract
The PTEN induced putative kinase 1 (PINK1) mutation is the second most common cause of autosomal recessive adolescent Parkinson's disease (PD). Furthermore, mitochondrial disorders and oxidative stress are important mechanisms in the pathogenesis of PD. Numerous members of the Wnt family have been found to be associated with neurodegenerative diseases. Therefore, the present study investigated the role of the Wnt2 gene in PINK1B9 transgenic flies, which is a PD model, and its underlying mechanism. It was identified that overexpression of Wnt2 reduced the abnormality rate of PD transgenic Drosophila and improved their flight ability, while other intervention groups had no significant effect. Furthermore, an increase in ATP concentration normalized mitochondrial morphology, and increased the mRNA expression levels of NADH‑ubiquinone oxidoreductase chain 1 (ND1), ND42, ND75, succinate dehydrogenase complex subunits B, Cytochrome b and Cyclooxygenase 1, which are associated with Wnt2 overexpression. Moreover, overexpression of Wnt2 in PD transgenic Drosophila resulted in the downregulation of reactive oxygen species and malondialdehyde production, and increased manganese superoxide dismutase (MnSOD), while glutathione was not significantly affected. It was found that overexpression of Wnt2 did not alter the protein expression of β‑catenin in PINK1B9 transgenic Drosophila, but did increase the expression levels of PPARG coactivator 1α (PGC‑1α) and forkhead box sub‑group O (FOXO). Collectively, the present results indicated that the Wnt2 gene may have a protective effect on PD PINK1B9 transgenic Drosophila. Thus, it was speculated that the reduction of oxidative stress and the restoration of mitochondrial function via Wnt2 overexpression may be related to the PGC‑1α/FOXO/MnSOD signaling pathway in PINK1 mutant transgenic Drosophila.
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Affiliation(s)
- Sui-Rui Xia
- Department of Hospital Infection‑Control, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi 541002, P.R. China
| | - Xue-Yi Wen
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Xiao-Li Fan
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Xiao-Rong Chen
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Zai-Wa Wei
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Qing-Hua Li
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Li Sun
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
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16
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Morton AJ, Middleton B, Rudiger S, Bawden CS, Kuchel TR, Skene DJ. Increased plasma melatonin in presymptomatic Huntington disease sheep (Ovis aries): Compensatory neuroprotection in a neurodegenerative disease? J Pineal Res 2020; 68:e12624. [PMID: 31742766 DOI: 10.1111/jpi.12624] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/05/2019] [Accepted: 11/14/2019] [Indexed: 01/09/2023]
Abstract
Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian-regulated hormones, melatonin and cortisol, in plasma samples collected around-the-clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN-driven rhythms and the effect of genotype, sex and age. Melatonin-related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)-mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD.
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Affiliation(s)
- A Jennifer Morton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Benita Middleton
- Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Skye Rudiger
- South Australian Research and Development Institute, Roseworthy, South Australia, Australia
| | - C Simon Bawden
- South Australian Research and Development Institute, Roseworthy, South Australia, Australia
| | - Timothy R Kuchel
- Preclinical, Imaging and Research Laboratories (PIRL), SAHMRI, Adelaide, South Australia, Australia
| | - Debra J Skene
- Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
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17
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Lloret A, Beal MF. PGC-1α, Sirtuins and PARPs in Huntington's Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All. Neurochem Res 2019; 44:2423-2434. [PMID: 31065944 DOI: 10.1007/s11064-019-02809-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/02/2019] [Accepted: 05/02/2019] [Indexed: 12/20/2022]
Abstract
In this review, we summarize the available published information on the neuroprotective effects of increasing nicotinamide adenine dinucleotide (NAD+) levels in Huntington's disease models. We discuss the rationale of potential therapeutic benefit of administering nicotinamide riboside (NR), a safe and effective NAD+ precursor. We discuss the agonistic effect on the Sirtuin1-PGC-1α-PPAR pathway as well as Sirtuin 3, which converge in improving mitochondrial function, decreasing ROS production and ameliorating bioenergetics deficits. Also, we discuss the potential synergistic effect of increasing NAD+ combined with PARPs inhibitors, as a clinical therapeutic option not only in HD, but other neurodegenerative conditions.
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Affiliation(s)
- Alejandro Lloret
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1400 York Street, 5th Floor, Room A-501, New York, NY, 10065, USA.
- NeuCyte Pharmaceuticals, 1561 Industrial Road, San Carlos, CA, 94070, USA.
| | - M Flint Beal
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1400 York Street, 5th Floor, Room A-501, New York, NY, 10065, USA
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18
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Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view. Prog Neurobiol 2019; 181:101645. [PMID: 31229499 DOI: 10.1016/j.pneurobio.2019.101645] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/03/2019] [Accepted: 06/18/2019] [Indexed: 12/11/2022]
Abstract
Neurodegenerative diseases (NDDs), which are among the most important aging-related diseases, are typically characterized by neuronal damage and a progressive impairment in neurological function during aging. Few effective therapeutic targets for NDDs have been revealed; thus, an understanding of the pathogenesis of NDDs is important. Forkhead box O (FoxO) transcription factors have been implicated in the mechanisms regulating aging and longevity. The functions of FoxOs are regulated by diverse post-translational modifications (e.g., phosphorylation, acetylation, ubiquitination, methylation and glycosylation). FoxOs exert both detrimental and protective effects on NDDs. Therefore, an understanding of the precise function of FoxOs in NDDs will be helpful for developing appropriate treatment strategies. In this review, we first introduce the post-translational modifications of FoxOs. Next, the regulation of FoxO expression and post-translational modifications in the central nervous system (CNS) is described. Afterwards, we analyze and address the important roles of FoxOs in NDDs. Finally, novel potential directions of future FoxO research in NDDs are discussed. This review recapitulates essential facts and questions about the promise of FoxOs in treating NDDs, and it will likely be important for the design of further basic studies and to realize the potential for FoxOs as therapeutic targets in NDDs.
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19
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Wang D, Luo Y, Wang G, Yang Q. Circular RNA expression profiles and bioinformatics analysis in ovarian endometriosis. Mol Genet Genomic Med 2019; 7:e00756. [PMID: 31144476 PMCID: PMC6637292 DOI: 10.1002/mgg3.756] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 12/16/2022] Open
Abstract
Background Circular RNAs (circRNAs) with miRNA response elements (MREs) could function as competing endogenous RNA (ceRNA) in regulating gene expression, thus playing vital roles in pathogenesis and progression of many diseases. However, the function of circRNAs in endometriosis remains unknown. This study was carried to profile the expression patterns of circRNAs in ovarian endometriosis. Methods High throughput RNA‐Seq was performed in six paired ectopic and eutopic endometrium tissues (ecEM vs. euEM), followed by quantitative real‐time polymerase chain reaction (qRT‐PCR) in 30 paired samples. Through bioinformatics prediction, we constructed a circRNA‐miRNA ‐mRNA network and elucidated circRNAs functions by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results A total of 146 upregulated and 148 downregulated circRNAs were identified, binding with 2,495 MREs. The qRT‐PCR validation results of four upregulated circRNAs matched the RNA‐Seq data. The ceRNA network included 48 miRNAs and 296 mRNAs. Functional analysis revealed several important pathways such as MAPK signaling pathway, and PI3K‐AKT signaling pathway, which might be associated with the pathogenesis and development of endometriosis. Conclusion Our data suggested that circRNAs are differentially expressed in endometriosis, which might be candidate factors for pathogenesis of this disease and be considered as promising therapeutic targets in the future.
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Affiliation(s)
- Dandan Wang
- Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yajuan Luo
- Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Guangwei Wang
- Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qing Yang
- Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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20
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McLaughlin CN, Broihier HT. Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity. Trends Genet 2018; 34:65-78. [PMID: 29102406 DOI: 10.1016/j.tig.2017.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 12/27/2022]
Abstract
Any adult who has tried to take up the piano or learn a new language is faced with the sobering realization that acquiring such skills is more challenging as an adult than as a child. Neuronal plasticity, or the malleability of brain circuits, declines with age. Young neurons tend to be more adaptable and can alter the size and strength of their connections more readily than can old neurons. Myriad circuit- and synapse-level mechanisms that shape plasticity have been identified. Yet, molecular mechanisms setting the overall competence of young neurons for distinct forms of plasticity remain largely obscure. Recent studies indicate evolutionarily conserved roles for FoxO proteins in establishing the capacity for cell-fate, morphological, and synaptic plasticity in neurons.
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Affiliation(s)
- Colleen N McLaughlin
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Heather T Broihier
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
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21
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Baldo B, Gabery S, Soylu-Kucharz R, Cheong RY, Henningsen JB, Englund E, McLean C, Kirik D, Halliday G, Petersén Å. SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease. Neuropathol Appl Neurobiol 2018; 45:361-379. [PMID: 30019499 DOI: 10.1111/nan.12514] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 07/11/2018] [Indexed: 01/03/2023]
Abstract
AIMS Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
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Affiliation(s)
- B Baldo
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - S Gabery
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - R Soylu-Kucharz
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - R Y Cheong
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - J B Henningsen
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - E Englund
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - C McLean
- Department of Pathology, Alfred Hospital, Melbourne, Vic, Australia
| | - D Kirik
- B.R.A.I.N.S. Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - G Halliday
- Brain and Mind Centre, Sydney Medical School, UNSW Medicine and NeuRA, The University of Sydney, Sydney, NSW, Australia
| | - Å Petersén
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
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22
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Maulik M, Mitra S, Hunter S, Hunstiger M, Oliver SR, Bult-Ito A, Taylor BE. Sir-2.1 mediated attenuation of α-synuclein expression by Alaskan bog blueberry polyphenols in a transgenic model of Caenorhabditis elegans. Sci Rep 2018; 8:10216. [PMID: 29976995 PMCID: PMC6033853 DOI: 10.1038/s41598-018-26905-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/22/2018] [Indexed: 01/22/2023] Open
Abstract
Misfolding and accumulation of cellular protein aggregates are pathological hallmarks of aging and neurodegeneration. One such protein is α-synuclein, which when misfolded, forms aggregates and disrupts normal cellular functions of the neurons causing Parkinson's disease. Nutritional interventions abundant in pharmacologically potent polyphenols have demonstrated a therapeutic role for combating protein aggregation associated with neurodegeneration. The current study hypothesized that Alaskan bog blueberry (Vaccinum uliginosum), which is high in polyphenolic content, will reduce α-synuclein expression in a model of Caenorhabditis elegans (C. elegans). We observed that blueberry extracts attenuated α-synuclein protein expression, improved healthspan in the form of motility and restored lipid content in the transgenic strain of C. elegans expressing human α-synuclein. We also found reduced gene expression levels of sir-2.1 (ortholog of mammalian Sirtuin 1) in blueberry treated transgenic animals indicating that the beneficial effects of blueberries could be mediated through partial reduction of sirtuin activity. This therapeutic effect of the blueberries was attributed to its xenohormetic properties. The current results highlight the role of Alaskan blueberries in mediating inhibition of sir-2.1 as a novel therapeutic approach to improving pathologies of protein misfolding diseases. Finally, our study warrants further investigation of the structure, and specificity of such small molecules from indigenous natural compounds and its role as sirtuin regulators.
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Affiliation(s)
- Malabika Maulik
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK, USA.
| | - Swarup Mitra
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK, USA
- Department of Pharmacology and Toxicology, The Research Institution on Addictions, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Skyler Hunter
- Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Moriah Hunstiger
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - S Ryan Oliver
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Abel Bult-Ito
- Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Barbara E Taylor
- Department of Biological Sciences and College of Natural Sciences and Mathematics, California State University, Long Beach, Long Beach, CA, USA.
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23
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Ament SA, Pearl JR, Cantle JP, Bragg RM, Skene PJ, Coffey SR, Bergey DE, Wheeler VC, MacDonald ME, Baliga NS, Rosinski J, Hood LE, Carroll JB, Price ND. Transcriptional regulatory networks underlying gene expression changes in Huntington's disease. Mol Syst Biol 2018; 14:e7435. [PMID: 29581148 PMCID: PMC5868199 DOI: 10.15252/msb.20167435] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/23/2018] [Accepted: 02/26/2018] [Indexed: 12/19/2022] Open
Abstract
Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF-target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found CAG repeat length-dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD.
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Affiliation(s)
- Seth A Ament
- Institute for Systems Biology, Seattle, WA, USA
- Institute for Genome Sciences and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jocelynn R Pearl
- Institute for Systems Biology, Seattle, WA, USA
- Molecular & Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA
- Altius Institute for Biomedical Sciences, Seattle, WA, USA
| | - Jeffrey P Cantle
- Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA
| | - Robert M Bragg
- Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA
| | - Peter J Skene
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sydney R Coffey
- Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA
| | | | - Vanessa C Wheeler
- Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Marcy E MacDonald
- Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Jim Rosinski
- CHDI Management, CHDI Foundation, Princeton, NJ, USA
| | | | - Jeffrey B Carroll
- Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA
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24
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Elibol B, Kilic U. High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions. Front Endocrinol (Lausanne) 2018; 9:614. [PMID: 30374331 PMCID: PMC6196295 DOI: 10.3389/fendo.2018.00614] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/27/2018] [Indexed: 01/11/2023] Open
Abstract
SIRT1 protein, a member of Silent Information Regulator 2 (Sir2) protein family, have gained considerable attention as epigenetic regulators for a great area in the human physiology. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, cardiovascular diseases, cancer and neurodegeneration. Here, we provide an overview of the association of the increasing level of SIRT1 protein for regulating some disease related conditions such as obesity, cardiovascular diseases and neurodegeneration. This review also provides a detailed molecular understanding of the interaction of the some basic molecules with increasing SIRT1 levels rather than reduction of the SIRT1 expression. In this context, the current approaches to enhancing the expression of SIRT1 points the importance of epigenetics in several age-related diseases to provide a healthy aging by developing novel therapies which can prevent or damp the progression of some diseases.
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Affiliation(s)
- Birsen Elibol
- Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ulkan Kilic
- Department of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
- *Correspondence: Ulkan Kilic
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25
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Chongtham A, Barbaro B, Filip T, Syed A, Huang W, Smith MR, Marsh JL. Nonmammalian Models of Huntington's Disease. Methods Mol Biol 2018; 1780:75-96. [PMID: 29856015 DOI: 10.1007/978-1-4939-7825-0_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Flies, worms, yeast and more recently zebra fish have all been engineered to express expanded polyglutamine repeat versions of Huntingtin with various resulting pathologies including early death, neurodegeneration, and loss of motor function. Each of these models present particular features that make it useful in studying the mechanisms of polyglutamine pathology. However, one particular unbiased readout of mHTT pathology is functional loss of motor control. Loss of motor control is prominent in patients, but it remains unresolved whether pathogenic symptoms in patients result from overt degeneration and loss of neurons or from malfunctioning of surviving neurons as the pathogenic insult builds up. This is why a functional assay such as motor control can be uniquely powerful in revealing early as well as late neurological deficits and does not rely on assumptions such as that the level of inclusions or the degree of neuronal loss can be equated with the level of pathology. Drosophila is well suited for such assays because it contains a functioning nervous system with many parallels to the human condition. In addition, the ability to readily express mHTT transgenes in different tissues and subsets of neurons allows one the possibility of isolating a particular effect to a subset of neurons where one can correlate subcellular events in response to mHTT challenge with pathology at both the cellular and organismal levels. Here we describe methods to monitor the degree of motor function disruption in Drosophila models of HD and we include a brief summary of other nonmammalian models of HD and discussion of their unique strengths.
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Affiliation(s)
- Anjalika Chongtham
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA
| | - Brett Barbaro
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA.,The Scripps Research Institute, La Jolla, CA, USA
| | - Tomas Filip
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA.,Biology Centre Czech Acad. Sci., Ceske Budejovice, Czech Republic
| | - Adeela Syed
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA
| | - Weijian Huang
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA
| | - Marianne R Smith
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA.,University Advancement, UC Irvine, Irvine, CA, USA
| | - J Lawrence Marsh
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697, CA, USA.
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26
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Abstract
In mammals, recent studies have demonstrated that the brain, the hypothalamus in particular, is a key bidirectional integrator of humoral and neural information from peripheral tissues, thus influencing ageing both in the brain and at the 'systemic' level. CNS decline drives the progressive impairment of cognitive, social and physical abilities, and the mechanisms underlying CNS regulation of the ageing process, such as microglia-neuron networks and the activities of sirtuins, a class of NAD+-dependent deacylases, are beginning to be understood. Such mechanisms are potential targets for the prevention or treatment of age-associated dysfunction and for the extension of a healthy lifespan.
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27
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Farina F, Lambert E, Commeau L, Lejeune FX, Roudier N, Fonte C, Parker JA, Boddaert J, Verny M, Baulieu EE, Neri C. The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington's disease. Sci Rep 2017. [PMID: 28638078 PMCID: PMC5479833 DOI: 10.1038/s41598-017-04256-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington’s disease (HD), Parkinson’s disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.
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Affiliation(s)
- Francesca Farina
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
| | - Emmanuel Lambert
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
| | - Lucie Commeau
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
| | - François-Xavier Lejeune
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
| | | | - Cosima Fonte
- Inserm, UMR 1195, 94276, Le Kremlin-Bicêtre, Cedex, France
| | - J Alex Parker
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.,CRCHUM, Montréal, Canada and Department de Neurosciences, Faculté de médecine, Université de Montréal, Montréal, Canada
| | - Jacques Boddaert
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.,Department of Geriatrics, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris (APHP), 75013, Paris, France
| | - Marc Verny
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France.,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.,Department of Geriatrics, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris (APHP), 75013, Paris, France
| | - Etienne-Emile Baulieu
- Inserm, UMR 1195, 94276, Le Kremlin-Bicêtre, Cedex, France. .,MAPREG, 94276, Le Kremlin-Bicêtre, Cedex, France.
| | - Christian Neri
- CNRS, Laboratory of Neuronal Cell Biology & Pathology and University Hospital Department Fight Aging and Stress (DHU FAST), UMR 8256, Paris, France. .,Sorbonne Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.
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28
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Lee AL, Ung HM, Sands LP, Kikis EA. A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles. PLoS One 2017; 12:e0173644. [PMID: 28282438 PMCID: PMC5345860 DOI: 10.1371/journal.pone.0173644] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 02/22/2017] [Indexed: 11/29/2022] Open
Abstract
Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington’s Disease (HD) that is caused by a polyglutamine expansion in the human huntingtin protein (htt). The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.
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Affiliation(s)
- Amy L. Lee
- Biology Department, The University of the South, Sewanee, TN, United States of America
| | - Hailey M. Ung
- Biology Department, The University of the South, Sewanee, TN, United States of America
| | - L. Paul Sands
- Biology Department, The University of the South, Sewanee, TN, United States of America
| | - Elise A. Kikis
- Biology Department, The University of the South, Sewanee, TN, United States of America
- * E-mail:
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29
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Subramaniyan B, Jagadeesan K, Ramakrishnan S, Mathan G. Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review. Biomed Pharmacother 2016; 82:413-24. [DOI: 10.1016/j.biopha.2016.05.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 05/18/2016] [Accepted: 05/18/2016] [Indexed: 12/22/2022] Open
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30
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Scarpa JR, Jiang P, Losic B, Readhead B, Gao VD, Dudley JT, Vitaterna MH, Turek FW, Kasarskis A. Systems Genetic Analyses Highlight a TGFβ-FOXO3 Dependent Striatal Astrocyte Network Conserved across Species and Associated with Stress, Sleep, and Huntington's Disease. PLoS Genet 2016; 12:e1006137. [PMID: 27390852 PMCID: PMC4938493 DOI: 10.1371/journal.pgen.1006137] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 05/31/2016] [Indexed: 12/22/2022] Open
Abstract
Recent systems-based analyses have demonstrated that sleep and stress traits emerge from shared genetic and transcriptional networks, and clinical work has elucidated the emergence of sleep dysfunction and stress susceptibility as early symptoms of Huntington's disease. Understanding the biological bases of these early non-motor symptoms may reveal therapeutic targets that prevent disease onset or slow disease progression, but the molecular mechanisms underlying this complex clinical presentation remain largely unknown. In the present work, we specifically examine the relationship between these psychiatric traits and Huntington's disease (HD) by identifying striatal transcriptional networks shared by HD, stress, and sleep phenotypes. First, we utilize a systems-based approach to examine a large publicly available human transcriptomic dataset for HD (GSE3790 from GEO) in a novel way. We use weighted gene coexpression network analysis and differential connectivity analyses to identify transcriptional networks dysregulated in HD, and we use an unbiased ranking scheme that leverages both gene- and network-level information to identify a novel astrocyte-specific network as most relevant to HD caudate. We validate this result in an independent HD cohort. Next, we computationally predict FOXO3 as a regulator of this network, and use multiple publicly available in vitro and in vivo experimental datasets to validate that this astrocyte HD network is downstream of a signaling pathway important in adult neurogenesis (TGFβ-FOXO3). We also map this HD-relevant caudate subnetwork to striatal transcriptional networks in a large (n = 100) chronically stressed (B6xA/J)F2 mouse population that has been extensively phenotyped (328 stress- and sleep-related measurements), and we show that this striatal astrocyte network is correlated to sleep and stress traits, many of which are known to be altered in HD cohorts. We identify causal regulators of this network through Bayesian network analysis, and we highlight their relevance to motor, mood, and sleep traits through multiple in silico approaches, including an examination of their protein binding partners. Finally, we show that these causal regulators may be therapeutically viable for HD because their downstream network was partially modulated by deep brain stimulation of the subthalamic nucleus, a medical intervention thought to confer some therapeutic benefit to HD patients. In conclusion, we show that an astrocyte transcriptional network is primarily associated to HD in the caudate and provide evidence for its relationship to molecular mechanisms of neural stem cell homeostasis. Furthermore, we present a unified systems-based framework for identifying gene networks that are associated with complex non-motor traits that manifest in the earliest phases of HD. By analyzing and integrating multiple independent datasets, we identify a point of molecular convergence between sleep, stress, and HD that reflects their phenotypic comorbidity and reveals a molecular pathway involved in HD progression.
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Affiliation(s)
- Joseph R. Scarpa
- Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Peng Jiang
- Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America
| | - Bojan Losic
- Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Ben Readhead
- Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Vance D. Gao
- Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America
| | - Joel T. Dudley
- Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Martha H. Vitaterna
- Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America
| | - Fred W. Turek
- Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America
| | - Andrew Kasarskis
- Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
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31
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Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges. IMMUNITY & AGEING 2016; 13:16. [PMID: 27081392 PMCID: PMC4831196 DOI: 10.1186/s12979-016-0070-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 03/30/2016] [Indexed: 12/20/2022]
Abstract
An extensive literature describes the positive impact of dietary phytochemicals on overall health and longevity. Dietary phytochemicals include a large group of non-nutrients compounds from a wide range of plant-derived foods and chemical classes. Over the last decade, remarkable progress has been made to realize that oxidative and nitrosative stress (O&NS) and chronic, low-grade inflammation are major risk factors underlying brain aging. Accumulated data strongly suggest that phytochemicals from fruits, vegetables, herbs, and spices may exert relevant negative immunoregulatory, and/or anti-O&NS activities in the context of brain aging. Despite the translational gap between basic and clinical research, the current understanding of the molecular interactions between phytochemicals and immune-inflammatory and O&NS (IO&NS) pathways could help in designing effective nutritional strategies to delay brain aging and improve cognitive function. This review attempts to summarise recent evidence indicating that specific phytochemicals may act as positive modulators of IO&NS pathways by attenuating pro-inflammatory pathways associated with the age-related redox imbalance that occurs in brain aging. We will also discuss the need to initiate long-term nutrition intervention studies in healthy subjects. Hence, we will highlight crucial aspects that require further study to determine effective physiological concentrations and explore the real impact of dietary phytochemicals in preserving brain health before the onset of symptoms leading to cognitive decline and inflammatory neurodegeneration.
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32
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Vayndorf EM, Scerbak C, Hunter S, Neuswanger JR, Toth M, Parker JA, Neri C, Driscoll M, Taylor BE. Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis. NPJ Aging Mech Dis 2016; 2. [PMID: 27347427 PMCID: PMC4920063 DOI: 10.1038/npjamd.2016.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.
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Affiliation(s)
- Elena M Vayndorf
- Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Courtney Scerbak
- Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA; Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Skyler Hunter
- Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Jason R Neuswanger
- Warnell School of Forestry and Natural Resources, University of Georgia, Athens, GA, USA
| | - Marton Toth
- Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - J Alex Parker
- Department of Neuroscience, CRCHUM, University of Montreal, Montreal, QC, Canada
| | - Christian Neri
- Laboratory of Neuronal Cell Biology and Pathology, Centre National de la Recherche Scientifique, Paris, France; Sorbonnes Universités, UPMC Univ Paris 06, Paris, France
| | - Monica Driscoll
- Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Barbara E Taylor
- Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA; Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA
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Martin A, Tegla CA, Cudrici CD, Kruszewski AM, Azimzadeh P, Boodhoo D, Mekala AP, Rus V, Rus H. Role of SIRT1 in autoimmune demyelination and neurodegeneration. Immunol Res 2015; 61:187-97. [PMID: 25281273 DOI: 10.1007/s12026-014-8557-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD(+)-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders.
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Affiliation(s)
- Alvaro Martin
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
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Vázquez-Manrique RP, Farina F, Cambon K, Dolores Sequedo M, Parker AJ, Millán JM, Weiss A, Déglon N, Neri C. AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease. Hum Mol Genet 2015; 25:1043-58. [PMID: 26681807 PMCID: PMC4764188 DOI: 10.1093/hmg/ddv513] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Accepted: 12/10/2015] [Indexed: 12/25/2022] Open
Abstract
The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD.
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Affiliation(s)
- Rafael P Vázquez-Manrique
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France, Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain,
| | - Francesca Farina
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
| | - Karine Cambon
- Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France
| | - María Dolores Sequedo
- Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Alex J Parker
- CRCHUM, Montréal, Canada, Department de Neurosciences, Faculté de médecine, Université de Montréal, Montréal, Canada
| | - José María Millán
- Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Andreas Weiss
- Evotec AG, Manfred Eigen Campus, Hamburg, Germany and
| | - Nicole Déglon
- Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Department of Clinical Neurosciences (DNC), Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Christian Neri
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France,
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Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: A critical appraisal. World J Diabetes 2015; 6:1223-1242. [PMID: 26464760 PMCID: PMC4598605 DOI: 10.4239/wjd.v6.i12.1223] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/25/2015] [Accepted: 09/08/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer’s disease (AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, biochemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.
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Szlachcic WJ, Switonski PM, Krzyzosiak WJ, Figlerowicz M, Figiel M. Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway. Dis Model Mech 2015; 8:1047-57. [PMID: 26092128 PMCID: PMC4582098 DOI: 10.1242/dmm.019406] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 06/11/2015] [Indexed: 12/27/2022] Open
Abstract
Huntington disease (HD) is a brain disorder characterized by the late onset of motor and cognitive symptoms, even though the neurons in the brain begin to suffer dysfunction and degeneration long before symptoms appear. There is currently no cure. Several molecular and developmental effects of HD have been identified using neural stem cells (NSCs) and differentiated cells, such as neurons and astrocytes. Still, little is known regarding the molecular pathogenesis of HD in pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Therefore, we examined putative signaling pathways and processes involved in HD pathogenesis in pluripotent cells. We tested naïve mouse HD YAC128 iPSCs and two types of human HD iPSC that were generated from HD and juvenile-HD patients. Surprisingly, we found that a number of changes affecting cellular processes in HD were also present in undifferentiated pluripotent HD iPSCs, including the dysregulation of the MAPK and Wnt signaling pathways and the dysregulation of the expression of genes related to oxidative stress, such as Sod1. Interestingly, a common protein interactor of the huntingtin protein and the proteins in the above pathways is p53, and the expression of p53 was dysregulated in HD YAC128 iPSCs and human HD iPSCs. In summary, our findings demonstrate that multiple molecular pathways that are characteristically dysregulated in HD are already altered in undifferentiated pluripotent cells and that the pathogenesis of HD might begin during the early stages of life.
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Affiliation(s)
- Wojciech J Szlachcic
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland
| | - Pawel M Switonski
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland
| | - Wlodzimierz J Krzyzosiak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland
| | - Marek Figlerowicz
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland
| | - Maciej Figiel
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań 61-704, Poland
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Scerbak C, Vayndorf EM, Parker JA, Neri C, Driscoll M, Taylor BE. Insulin signaling in the aging of healthy and proteotoxically stressed mechanosensory neurons. Front Genet 2014; 5:212. [PMID: 25101108 PMCID: PMC4107846 DOI: 10.3389/fgene.2014.00212] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 06/20/2014] [Indexed: 12/22/2022] Open
Abstract
Insulin signaling is central to cellular metabolism and organismal aging. However, the role of insulin signaling in natural and proteotoxically stressed aging neurons has yet to be fully described. We studied aging of Caenorbaditis elegans mechanosensory neurons expressing a neurotoxic expanded polyglutamine transgene (polyQ128), or lacking this proteotoxicity stressor (polyQ0), under conditions in which the insulin signaling pathway was disrupted by RNA interference (RNAi). We describe specific changes in lifespan, mechanosensory neuronal morphologies, and mechansensory function following RNAi treatment targeting the insulin signaling pathway. Overall, we confirmed that transcription factor DAF-16 is neuroprotective in the proteotoxically stressed model, though not strikingly in the naturally aging model. Decreased insulin signaling through daf-2 RNAi improved mechanosensory function in both models and decreased protein aggregation load in polyQ128, yet showed opposing effects on accumulation of neuronal aberrations in both strains. Decreased daf-2 signaling slightly enhanced mechanosensation while greatly enhancing branching of the mechanosensory neuron axons and dendrites in polyQ0 animals, suggesting that branching is an adaptive response in natural aging. These effects in polyQ0 did not appear to involve DAF-16, suggesting the existence of a non-canonical DAF-2 pathway for the modulation of morphological adaptation. However, in polyQ128 animals, decreased daf-2 signaling significantly enhanced mechanosensation while decreasing neuronal aberrations. Unlike other interventions that reduce the strength of insulin signaling, daf-2 RNAi dramatically redistributed large polyQ128 aggregates to the cell body, away from neuronal processes. Our results suggest that insulin signaling strength can differentially affect specific neurons aging naturally or under proteotoxic stress.
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Affiliation(s)
- Courtney Scerbak
- Institute of Arctic Biology, University of Alaska Fairbanks Fairbanks, AK, USA ; Department of Biology and Wildlife, University of Alaska Fairbanks Fairbanks, AK, USA
| | - Elena M Vayndorf
- Institute of Arctic Biology, University of Alaska Fairbanks Fairbanks, AK, USA
| | - J Alex Parker
- Department of Neuroscience, CRCHUM, University of Montreal Montreal, QC, Canada
| | - Christian Neri
- Laboratory of Neuronal Cell Biology and Pathology, Centre National de la Recherche Scientifique, UMR 8652 Paris, France ; Sorbonnes Universités, UPMC Univ Paris 06 Paris, France
| | - Monica Driscoll
- Nelson Biological Laboratories, Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey Piscataway, NJ, USA
| | - Barbara E Taylor
- Institute of Arctic Biology, University of Alaska Fairbanks Fairbanks, AK, USA ; Department of Biology and Wildlife, University of Alaska Fairbanks Fairbanks, AK, USA
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Giblin W, Skinner ME, Lombard DB. Sirtuins: guardians of mammalian healthspan. Trends Genet 2014; 30:271-86. [PMID: 24877878 PMCID: PMC4077918 DOI: 10.1016/j.tig.2014.04.007] [Citation(s) in RCA: 206] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 04/23/2014] [Accepted: 04/25/2014] [Indexed: 12/12/2022]
Abstract
The first link between sirtuins and longevity was made 15 years ago in yeast. These initial studies sparked efforts by many laboratories working in diverse model organisms to elucidate the relations between sirtuins, lifespan, and age-associated dysfunction. Here, we discuss the current understanding of how sirtuins relate to aging. We focus primarily on mammalian sirtuins SIRT1, SIRT3, and SIRT6, the three sirtuins for which the most relevant data are available. Strikingly, a large body of evidence now indicates that these and other mammalian sirtuins suppress a variety of age-related pathologies and promote healthspan. Moreover, increased expression of SIRT1 or SIRT6 extends mouse lifespan. Overall, these data point to important roles for sirtuins in promoting mammalian health, and perhaps in modulating the aging process.
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Affiliation(s)
- William Giblin
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mary E Skinner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - David B Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA.
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Lee J, Jo DG, Park D, Chung HY, Mattson MP. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharmacol Rev 2014; 66:815-68. [PMID: 24958636 PMCID: PMC4081729 DOI: 10.1124/pr.113.007757] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied.
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Affiliation(s)
- Jaewon Lee
- Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Republic of Korea (J.L., D.P., H.Y.C.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (D.-G.J.); Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland (M.P.M.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (M.P.M.)
| | - Dong-Gyu Jo
- Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Republic of Korea (J.L., D.P., H.Y.C.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (D.-G.J.); Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland (M.P.M.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (M.P.M.)
| | - Daeui Park
- Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Republic of Korea (J.L., D.P., H.Y.C.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (D.-G.J.); Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland (M.P.M.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (M.P.M.)
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Republic of Korea (J.L., D.P., H.Y.C.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (D.-G.J.); Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland (M.P.M.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (M.P.M.)
| | - Mark P Mattson
- Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Republic of Korea (J.L., D.P., H.Y.C.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (D.-G.J.); Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland (M.P.M.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (M.P.M.)
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Tourette C, Farina F, Vazquez-Manrique RP, Orfila AM, Voisin J, Hernandez S, Offner N, Parker JA, Menet S, Kim J, Lyu J, Choi SH, Cormier K, Edgerly CK, Bordiuk OL, Smith K, Louise A, Halford M, Stacker S, Vert JP, Ferrante RJ, Lu W, Neri C. The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 2014; 12:e1001895. [PMID: 24960609 PMCID: PMC4068980 DOI: 10.1371/journal.pbio.1001895] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 05/15/2014] [Indexed: 12/19/2022] Open
Abstract
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.
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Affiliation(s)
- Cendrine Tourette
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
- Assistance Publique-Hopitaux de Paris (AP-HP), Charles Foix Hospital, Functional Exploration Unit, Ivry-sur-Seine, France
| | - Francesca Farina
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Rafael P. Vazquez-Manrique
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Anne-Marie Orfila
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Jessica Voisin
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Sonia Hernandez
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Nicolas Offner
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - J. Alex Parker
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Sophie Menet
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
| | - Jinho Kim
- Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Jungmok Lyu
- University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America
| | - Si Ho Choi
- University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America
| | - Kerry Cormier
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Christina K. Edgerly
- Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Olivia L. Bordiuk
- Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Karen Smith
- VA Bedford Geriatric Research Education and Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts, United States of America
| | - Anne Louise
- Pasteur Institute, Cytometry Platform, Paris, France
| | - Michael Halford
- Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia
| | - Steven Stacker
- Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia
| | - Jean-Philippe Vert
- Mines ParisTech, Center for Computational Biology, Fontainebleau, France
- Curie Institute, Research Center, Paris, France
- INSERM, Unit 900, Paris, France
| | - Robert J. Ferrante
- Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Wange Lu
- University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America
| | - Christian Neri
- CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France
- Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France
- INSERM, Unit 894, Paris, France
- * E-mail:
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Gkikas I, Petratou D, Tavernarakis N. Longevity pathways and memory aging. Front Genet 2014; 5:155. [PMID: 24926313 PMCID: PMC4044971 DOI: 10.3389/fgene.2014.00155] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 05/10/2014] [Indexed: 12/28/2022] Open
Abstract
The aging process has been associated with numerous pathologies at the cellular, tissue, and organ level. Decline or loss of brain functions, including learning and memory, is one of the most devastating and feared aspects of aging. Learning and memory are fundamental processes by which animals adjust to environmental changes, evaluate various sensory signals based on context and experience, and make decisions to generate adaptive behaviors. Age-related memory impairment is an important phenotype of brain aging. Understanding the molecular mechanisms underlying age-related memory impairment is crucial for the development of therapeutic strategies that may eventually lead to the development of drugs to combat memory loss. Studies in invertebrate animal models have taught us much about the physiology of aging and its effects on learning and memory. In this review we survey recent progress relevant to conserved molecular pathways implicated in both aging and memory formation and consolidation.
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Affiliation(s)
- Ilias Gkikas
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion Crete, Greece
| | - Dionysia Petratou
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion Crete, Greece
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion Crete, Greece ; Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion Crete, Greece
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Abstract
Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals. These proteins also play an important role in maintaining neuronal health during aging. During neuronal development, the SIR2 ortholog SIRT1 is structurally important, promoting axonal elongation, neurite outgrowth, and dendritic branching. This sirtuin also plays a role in memory formation by modulating synaptic plasticity. Hypothalamic functions that affect feeding behavior, endocrine function, and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer's, Parkinson's, and motor neuron diseases, which may relate to its functions in metabolism, stress resistance, and genomic stability. Drugs that activate SIRT1 may offer a promising approach to treat these disorders.
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Zhang J, Feng X, Wu J, Xu H, Li G, Zhu D, Yue Q, Liu H, Zhang Y, Sun D, Wang H, Sun J. Neuroprotective effects of resveratrol on damages of mouse cortical neurons induced by β-amyloid through activation of SIRT1/Akt1 pathway. Biofactors 2014; 40:258-67. [PMID: 24132831 DOI: 10.1002/biof.1149] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Revised: 09/04/2013] [Accepted: 09/09/2013] [Indexed: 12/25/2022]
Abstract
Resveratrol (3,5,4'-tihydroxy-trans-stilbene), a polyphenolic phytoalexin found in the skin and seeds of grapes, has been reported to possess a wide range of biological and pharmacological activities including antioxidant, anti-inflammatory, and antimutagenic effects. The present study intended to explore the neuroprotective effects of resveratrol against Aβ25-35 -induced neurotoxicity of cultured mouse cortical neurons and the possible mechanisms involved. For this purpose, mouse cortical neurons were cultured and exposed to 30 μM Aβ25-35 in the absence or presence of resveratrol (5, 10, and 25 μM). In addition, the potential contribution of the SIRT1/Akt1 neuroprotective pathway in resveratrol-mediated protection against Aβ25-35 -induced neurotoxicity was also investigated. The results showed that resveratrol dose-dependently increased cell viability and reduced the number of apoptotic cells as measured by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) activity assay, reactive oxygen species (ROS) activity assay, and Hoechst/PI double staining. Further study revealed that resveratrol through activation of SIRT1/Akt1 to avert apoptosis. These findings raise the possibility that resveratrol may be a potent therapeutic compound against the neurodegenerative diseases.
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Affiliation(s)
- Jing Zhang
- Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China
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Estevez AO, Morgan KL, Szewczyk NJ, Gems D, Estevez M. The neurodegenerative effects of selenium are inhibited by FOXO and PINK1/PTEN regulation of insulin/insulin-like growth factor signaling in Caenorhabditis elegans. Neurotoxicology 2014; 41:28-43. [PMID: 24406377 PMCID: PMC3979119 DOI: 10.1016/j.neuro.2013.12.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/23/2013] [Accepted: 12/27/2013] [Indexed: 12/12/2022]
Abstract
Insulin/insulin-like signaling reduction alters selenium-induced neurodegeneration. Selenium induces nuclear translocation of DAF-16/FOXO3a. DAF-16 overexpression decreases GABAergic and cholinergic motor neuron degeneration. Loss of DAF-18/PTEN increases sensitivity to selenium-induced movement deficits. Glutathione requires DAF-18/PINK-1 to improve selenium-induced movement deficits. Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of Caenorhabditis elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the DAF-16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase 1) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro-pathologic disease process.
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Affiliation(s)
- Annette O Estevez
- Department of Neurology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
| | - Kathleen L Morgan
- Veterans Affairs Pittsburgh Healthcare System, Research and Development (151U), University Drive C, Pittsburgh, PA 15240, USA.
| | - Nathaniel J Szewczyk
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
| | - David Gems
- Institute of Healthy Ageing, and Department of Genetics, Evolution, and Environment, University College London, The Darwin Building, Gower Street, London WC1E 6BT, UK.
| | - Miguel Estevez
- Department of Neurology, University of Arizona College of Medicine, Tucson, AZ 85724, USA; Veterans Affairs Pittsburgh Healthcare System, Research and Development (151U), University Drive C, Pittsburgh, PA 15240, USA.
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Developmental drift as a mechanism for aging: lessons from nematodes. Biogerontology 2013; 14:693-701. [DOI: 10.1007/s10522-013-9462-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 08/30/2013] [Indexed: 01/16/2023]
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Parmentier F, Lejeune FX, Neri C. Pathways to decoding the clinical potential of stress response FOXO-interaction networks for Huntington's disease: of gene prioritization and context dependence. Front Aging Neurosci 2013; 5:22. [PMID: 23781200 PMCID: PMC3680703 DOI: 10.3389/fnagi.2013.00022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 05/27/2013] [Indexed: 01/06/2023] Open
Abstract
The FOXO family of transcription factors is central to the regulation of organismal longevity and cellular survival. Several studies have indicated that FOXO factors lie at the center of a complex network of upstream pathways, cofactors and downstream targets (FOXO-interaction networks), which may have developmental and post-developmental roles in the regulation of chronic-stress response in normal and diseased cells. Noticeably, FOXO factors are important for the regulation of proteotoxicity and neuron survival in several models of neurodegenerative disease, suggesting that FOXO-interaction networks may have therapeutic potential. However, the status of FOXO-interaction networks in neurodegenerative disease remains largely unknown. Systems modeling is anticipated to provide a comprehensive assessment of this question. In particular, interrogating the context-dependent variability of FOXO-interaction networks could predict the clinical potential of cellular-stress response genes and aging regulators for tackling brain and peripheral pathology in neurodegenerative disease. Using published transcriptomic data obtained from murine models of Huntington's disease (HD) and post-mortem brains, blood samples and induced-pluripotent-stem cells from HD carriers as a case example, this review briefly highlights how the biological status and clinical potential of FOXO-interaction networks for HD may be decoded by developing network and entropy based feature selection across heterogeneous datasets.
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Affiliation(s)
- Frédéric Parmentier
- Laboratory of Neuronal Cell biology and Pathology, INSERM Unit 894, CNRS UMR 7102, University Pierre and Marie Curie Paris, France
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Shin BH, Lim Y, Oh HJ, Park SM, Lee SK, Ahnn J, Kim DH, Song WK, Kwak TH, Park WJ. Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy. PLoS One 2013; 8:e64953. [PMID: 23762270 PMCID: PMC3677867 DOI: 10.1371/journal.pone.0064953] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 04/19/2013] [Indexed: 12/14/2022] Open
Abstract
Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington’s disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). β-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, β-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. β-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by β-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of β-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, β-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that β-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, β-lap provides a novel therapeutic opportunity for the treatment of HD.
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Affiliation(s)
- Bae Hyun Shin
- Global Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Yunki Lim
- College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Hye Jin Oh
- College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Sang Min Park
- Global Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Sun-Kyung Lee
- Department of Life Science, Hanyang University, Seoul, Korea
- The Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Joohong Ahnn
- Department of Life Science, Hanyang University, Seoul, Korea
| | - Do Han Kim
- College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Woo Keun Song
- College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | | | - Woo Jin Park
- Global Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
- * E-mail:
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Abstract
Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.
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Affiliation(s)
- Adrianna Z Herskovits
- Department of Pathology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA
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49
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Abstract
The nematode Caenorhabditis elegans (C. elegans) has four Sir2 paralogs, sir-2.1, sir-2.2, sir-2.3, and sir-2.4. Thus far, most of the research tools to study worm sirtuins have been developed for sir-2.1, due to its homology to yeast SIR2 and human SIRT1. Here, we have compiled a listing of the currently available strains (including both loss-of-function alleles and transgenics), antibodies, and RNAi constructs relevant to studies on all C. elegans sirtuin family members. We also describe the methods used in the analysis of C. elegans sirtuin function, including life span analysis, various stress-resistance assays, and fat content analysis and provide an overview of all phenotypic data relevant to C. elegans sir-2.1.
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Affiliation(s)
- Mohan Viswanathan
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
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Tauffenberger A, Chitramuthu BP, Bateman A, Bennett HPJ, Parker JA. Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington's disease models. Hum Mol Genet 2012; 22:782-94. [PMID: 23172908 DOI: 10.1093/hmg/dds485] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The DNA/RNA binding proteins TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) are genetically linked to amyotrophic lateral sclerosis and frontotemporal lobar dementia, while the inappropriate cytoplasmic accumulations of TDP-43 and FUS are observed in a growing number of late-onset pathologies including spinocerebellar ataxia 3, Alzheimer's and Huntington's diseases (HD). To investigate if TDP-43 and FUS contribute to neurodegenerative phenotypes, we turned to a genetically accessible Caenorhabditis elegans model of polyglutamine toxicity. In C. elegans, we observe that genetic loss-of-function mutations for nematode orthologs of TDP-43 or FUS reduced behavioral defects and neurodegeneration caused by huntingtin exon-1 with expanded polyglutamines. Furthermore, using striatal cells from huntingtin knock-in mice we observed that small interfering ribonucleic acid (siRNA) against TDP-43 or FUS reduced cell death caused by mutant huntingtin. Moreover, we found that TDP-43 and the survival factor progranulin (PGRN) genetically interact to regulate polyglutamine toxicity in C. elegans and mammalian cells. Altogether our data point towards a conserved function for TDP-43 and FUS in promoting polyglutamine toxicity and that delivery of PGRN may have therapeutic benefits.
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